Vitamin B12, or cobalamin (cbl), is essential for healthy functioning of the human nervous system and red blood cell synthesis. Unable to produce the vitamin itself, the human body has to obtain it from animal-based foods such as milk products, eggs, red meat, chicken, fish, and shellfish - or vitamin supplements. Vitamin B12 is not found in vegetables.

Rare hereditary recessive diseases were thought to be expressed in off-spring only when both parents carry a mutation in the causal gene, but a new study is changing this paradigm. An international research team discovered a new cause of a rare condition known as cblC, that they named "epi-cblC". They reported it in patients from Europe and the United States. Patients who have cblC are not able to process vitamin B12, leading to severe health problems.

cblC is usually caused by two mutations - one inherited from each parent - in a gene called MMACHC. In some patients, the scientists found this disease actually results from a mutation on a single copy of the gene and the silencing of the second copy by a gene modification referred to as epimutation. This epimutation is produced by a mutation in an adjacent gene. Their findings, which were published in Nature Communications, may have an impact on diagnosis, and genetic counselling in families with genetic diseases, as well as in the development of new therapeutic approaches.

"We described a distinct and totally new mechanism referred as epi-cblC, whereby an epimutation causes abnormal regulation of the expression of an important vitamin B12 gene. This can result in a serious genetic disease that can cause anemia, neuro-cognitive impairment, and even early death," says the study's lead-author.

cblC is the most common of the inborn genetic errors of vitamin B12 metabolism. Based on one newborn patient case, who died from clinical implications of this disease, the scientists identified an epimutation affecting the MMACHC gene that was present in three generations and in the sperm of the fathers of two of the seven patients. They subsequently found it in other cases from Europe and North America and discovered that it resulted from the altered reading of the adjacent gene.

MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC.

"This epimutation observed in patients causes MMACHC to shut down and become inactive. This has the same effect as an actual mutation in the gene itself. This mechanism may be involved in many more diseases," explains study's co-author.

In previous work, the researchers discovered that mutations in the MMACHC gene were responsible for the cblC inborn error of vitamin B12metabolism. Following the study of several hundred patients, there remained a small number in whom only one mutation could be found in MMACHC.

Geneticists and molecular biologists will now need to look for epimutations in patients who have severe forms of rare diseases despite the lack of mutation in one of the two copies of the gene. The mechanism responsible for epimutation involves the two neighbouring genes of MMACHC, the gene responsible for the disease. Epigenetic mechanisms can also be caused by the environment (diet, stress, exposure to toxic products), and not by the chance of genetic mutations.

"We have identified some 40 rare diseases where this mechanism can be produced at the level of similar trios of genes," says the author.